DESCRIPTION Alzheimer's disease (AD) is a progressive cognitive deterioration which encompasses not only memory loss, but dementia. Neuropathologic hallmarks include a decline in density of synapses, cell loss, neuritic plaques, neurofibrillary tangles (NFT) and neuropil threads (NT). A stereotypic distribution of NFT and NT pathology parallels the progression of the disease. One of the earliest regions involved appears to be the entorhinal cortex/hippocampal complex. As the disease progresses, the temporal cortex becomes involved, followed by the frontal and parietal association areas, and finally, primary sensory and motor regions. A major correlate of dementia severity appears to be loss of synapses in cortical association areas. The loss of synapses causes a functionally important disconnection between regions of the neocortex. Progressive accumulation of NFT and NT, in distinct regions of the cortex, signals the ongoing loss of these corticocortical connections, which are the backbone of normal cognition. The NFT and NT pathology observed in AD is primarily restricted to cortical laminae III and V. These laminae receive and project important corticocortical information. It is unclear what the relationship is between NFT and NT neuropathology and the density of synapses during the progression of staging of the disease. A loss of synaptic density within a region of the cortex should be related to the density of neurons in that same region and also relate to the neuropathology. Areas affected very late in the disease should show less pathology and proportionally less neuronal loss and synapse loss. This grant will test the hypothesis that alterations in the density of synapses parallel the staging of AD pathology and the degree of cell loss and cytoskeletal changes. Specific aim #1 will determine the density of synapses in laminae III and V of specific regions of the brain known to be affected at different stages of the disease. Specific aim #2 will determine the relationship of laminar cytoskeletal changes to the density of synapses in specific regions of the brain affected at different stages of the disease. Specific aim #3 will determine the relationship of the laminar density of neurons to the density of synapses and cytoskeletal changes at different stages of the disease. Specific aim #4 will determine the possible relationship between free radical formation and changes in synaptic density. One of the novel proposed mechanisms for cellular damage in aging and AD is the formation of free radicals.